Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

Popovich, Irina G.; Anisimov, Vladimir N.; Zabezhinski, Mark A.; Semenchenko, Anna V.; Tyndyk, Margarita L.; Yurova, Maria N.; Blagosklonny, Mikhail V.

doi:10.4161/cbt.28164

Cited by 73 publications

(51 citation statements)

References 52 publications

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“…To further validate that mammosphere formation is functionally dependent on protein synthesis, we next used a well-established FDA-approved drug that potently inhibits protein synthesis, namely rapamycin [21-23]. Figure 6 shows the effects of increasing concentrations of rapamycin on mammosphere formation.…”

Section: Resultsmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than “bulk” cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.

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Section: Resultsmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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show abstract

“…[6][7][8][9][10] In agreement, rapamycin extends life span in mice. [11][12][13][14][15][16][17][18][19][20][21] However, this does not mean that the activity of mTOR is necessarily increased in old mice compared with young mice. In fact, even unchanged mTOR activity would be excessive in old animals compared with young, growing animals.…”

Section: Mtor and Agingmentioning

confidence: 99%

Fasting levels of hepatic p-S6 are increased in old mice

2014

Self Cite

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“…For example, rapamycin has emerged as a promising anti-tumor therapy in some malignancies (Dibble and Manning 2013). Moreover, a reduction in tumor formation has been noted in rapamycin-fed mice (Anisimov et al, 2010; Komarova et al, 2012; Popovich et al, 2014), which suggests that reduced tumor formation may underlie lifespan extension seen in normal mice (Sharp and Richardson 2011). However, rapamycin also has ameliorative effects on degenerative disease states that are clearly not associated with enhanced proliferation.…”

Section: Introductionmentioning

confidence: 99%

Aberrant mTOR activation in senescence and aging: A mitochondrial stress response?

Nacarelli

Azar

Sell

2015

Experimental Gerontology

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Unexpected activation of mTOR signaling, measured by ribosomal S6 phosphorylation or ribosomal S6 kinase (p70S6K) activity, has been reported in aging-related settings. Evidence of elevated mTOR activity has been reported in heart and muscle tissue in aged mice and humans, mouse models of progeria, and senescent human fibroblasts. We explore these reports and the possibility that activation of the mTOR/p70S6K kinase pathway may represent a ROS-mediated response to mitochondrial stress leading to the activation of senescence. This activation is a hallmark of both aged tissue and senescent human cells.

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Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

Cited by 73 publications

References 52 publications

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Fasting levels of hepatic p-S6 are increased in old mice

Aberrant mTOR activation in senescence and aging: A mitochondrial stress response?

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